Identifying the role of TALK-1 channels in islet hormone secretion, mitochondrial function, and the ER stress response.

Abstract

The two-pore domain K+ channel, TALK-1 modulates pancreatic β- and δ-cell Ca2+ ([Ca2+]c) entry and endoplasmic reticulum (ER) Ca2+ ([Ca2+]ER) handling thereby impacting hormone secretion and glucose tolerance. To investigate the cell specific mechanisms of TALK-1 we selectively ablated TALK-1 in β-cells (β-TALK1-KO) or δ-cells (δ-TALK1-KO). Although β-TALK1-KO mice show normal glucose tolerance on a chow diet, following exposure to a high-fat-diet (HFD) β-TALK1-KO mice showed improved glucose tolerance compared to controls. In contrast, δ-TALK1-KO mice did not show any changes in glucose tolerance but had improved fasting blood glucose levels on a HFD. Interestingly, β-TALK1-KO mice on a HFD had lower serum insulin levels compared to controls that was due to reduced islet glucose-stimulated insulin secretion (GSIS). This suggests that -cell TALK-1 channels control of GSIS may influence tissue insulin signaling or sensitivity. We next determined how TALK-1 control of [Ca2+]c handling impacts mitochondrial function. β-TALK1-KO islets have significantly increased [Ca2+]c oscillation frequency and greater [Ca2+]mito, which may result from either elevated [Ca2+]c or increased [Ca2+]ER storage. Ablation of β-cell TALK-1 also caused mitochondrial hyperpolarization and increased ATP production that could not be further enhanced following exposure to a HFD, which suggests that TALK-1 activity tunes beta-cell metabolism. As loss of TALK-1 function improves -cell function, a gain-of-function (GOF) in TALK-1 would be predicted to impair GSIS. To test this, we examined a dominant mutation in TALK-1(L114P), associated with maturity onset diabetes of the young. TALK-1-L114P results in a drastic GOF at the plasma membrane, hyperpolarizing the -cell membrane potential, limiting [Ca2+]c influx, reducing [Ca2+]ER storage, and inhibiting islet GSIS. We also examined a recessive mutation TALK-1(R13Q) that was associated with neonatal diabetes. Interestingly, in contrast to TALK-1(L114P), TALK-1(R13Q) abolished K+ currents at the plasma membrane possibly by limiting TALK-1 trafficking to the membrane. However, TALK-1(R13Q) maintained current on the ER membrane, reduced [Ca2+]ER storage, blunted β-cell glucose-stimulated [Ca2+]c influx, and limited GSIS. As these mutations in TALK-1 activity severely impact -cell function, this suggests that TALK-1 could be a therapeutic target for treating diabetes.